tbuckley/cabot-search huggingface dataset:
Abstract 1805: Identification of a small molecule that induces targeted protein degradation of ADAR1
Authors: Yuan Liu, Mads B. Larsen, Bo Lin, Jason R. Kennerdell, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen
Journal: Cancer Research (2023)

Abstract Adenosine deaminase acting on RNA (ADAR) are a family of enzymes that catalyzes the posttranscriptional conversion of adenosine to inosine in double-stranded RNA (dsRNA). Recent evidence suggests that genetic deletion of ADAR1 render tumors cells substantially more vulnerable to immunotherapy. In cells, ADAR1 is expressed as two different isoforms, the constitutively expressed ADAR1p110 and the inducible ADAR1p150. Evidence suggests that ADAR1p150 is the isoform that confers oncogenic and immune modulating effects in most tumors. Of note, many of the effects of ADAR1p150 appear to be independent of the protein’s RNA editing function suggesting that a small molecule which induces ADAR1p150 targeted protein degradation might be preferable to agents that simply block deaminase activity. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bind to the unique N-terminal region of ADAR1p150. One such molecule, CL-AD-100, directly bound to ADAR1p150 but not ADAR1p110. Moreover, sub-micromolar concentrations of CL-AD-100, induced proteasomal mediated degradation of ADAR1p150, without effecting ADAR1p110 expression. Cells treated with CL-AD-100 exhibited a signature consistent with what has been observed with ADAR1p150 genetic deletion, namely accumulation of dsRNA, an inflammatory gene expression profile and interferon-dependent cell death. These results therefore demonstrate the feasibility of generating a small molecule that induces the specific targeted protein degradation of ADAR1p150. Such a molecule should have wide applicability in ADAR1-addicted tumors, as well as more broadly, in immuno-oncology. Citation Format: Yuan Liu, Mads B. Larsen, Bo Lin, Jason R. Kennerdell, Irene Alfaras, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a small molecule that induces targeted protein degradation of ADAR1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1805.
Abstract 2806: Patient-derived cell-based pharmacogenomic platform to uncover resistance mechanisms and novel therapeutics for advanced lung cancer
Authors: Charny Park, Namhee Yu, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Sehwa Hong, Sunshin Kim, Ji-Youn Han
Journal: Cancer Research (2023)

Abstract To uncover resistance mechanism and effective drugs for advanced lung cancer patients, we stablished a pharmacogenomic platform using patient-derived cells (PDC). Drug response screening and multi-omics datasets were obtained from lung cancer PDCs (n=102). We interrogated sensitive drugs from variant, gene expression, and clinical profiles. Machine learning approaches were applied to extract molecular target signatures and pathways associated with sensitive drugs. Next, acquired resistance pathways and drug candidates were investigated from patients to receive serial EGFR-TKI treatments. Our PDC model resembled with TCGA genomic profile. Three RNA subtypes were identified from gene expression: (1) MYC, (2) epithelial-to-mesenchymal (EMT), and (3) inflammatory activation. Drugs for mutations and subtypes were extracted. Especially, SCLC harboring both TP53 and RB1 mutations was abundant in RNA subtype 1 and showed sensitivity to cell cycle inhibitors. Among EGFR-TKI treatment groups, Osimertinib resistant group was enriched in EMT-like subtype 2 with vanishing EGFR T790M mutation and activating TGF-β pathway. The group showed sensitivity to YAP/TAZ inhibitor. Our PDC pharmacogenetic platform predict plausible drug candidates and markers for refractory lung cancer patients. We expect further studies for precision medicine by novel analysis and cohort expansion. Citation Format: Charny Park, Namhee Yu, Mihwa Hwang, Youngjoo Lee, Bo Ram Song, Eun Hye Kang, Hanna Sim, Beung-Chul Ahn, Kum Hui Hwang, Sehwa Hong, Sunshin Kim, Ji-Youn Han. Patient-derived cell-based pharmacogenomic platform to uncover resistance mechanisms and novel therapeutics for advanced lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2806.
Abstract 4062: The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy
Authors: Yarong Liu, Jingwei Sun, Yao Sheng, Jingman Wang, Jiahui Jin, Fei Li, Lingyun Chen, Di Zhou, Yongchao Tan, Quanwei Wang, Zhao Xu, Haibao Li, Pin Wang, Jun Cui
Journal: Cancer Research (2023)

Abstract Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic effects in multiple types of solid tumors and significantly prolonged the survival of late-stage patients. However, the “prone-to-exhaustion” phenotype of the final TIL product after rapid expansion during manufacture and the presence of various immunosuppressive mechanisms in tumor microenvironment (TME) compromises the persistence and anti-tumor efficacy of TIL post infusion. To discover potential immunoregulatory targets that could maximize the function of TIL, we established a genome-wide CRISPR/Cas9 screening platform, ImmuT Finder®, to unbiasedly identify functional gene targets in primary T cells. Notably, this platform employed T cells bearing a tumor-antigen specific TCR-T that were repeatedly stimulated by tumor cells with cognate tumor antigen and demonstrated similar exhaustion profile as TIL. We selected top 30 targets after several rounds of screening and quickly validated their function in a 96-well array. Then, the top targets that showed significantly enhancement in proliferation and function of TCR-T were further selected, and their combinational effects on TIL were tested both in vitro and in vivo. Finally, double KO of GT304 and GT312 (GT316) stands out as the most potent combination, which significantly improves TIL proliferation and cytokine release, eradicates tumor growth in both CDX and PDX mouse models and promotes long-term in vivo persistence with low-dependence on IL-2. Specific and potent sgRNAs targeting both targets have been selected, and manufacturing process of GT316 TIL product has been developed (KOReTIL®). In summary, these data demonstrated that our ImmuT Finder® platform enables unbiased discovery of potent and novel targets for the development of T cell therapy and support the clinical assessment of GT316 as a next-generation TIL therapy. Currently, an investigator-initiated trial of GT316 is ongoing in China. Citation Format: Yarong Liu, Jingwei Sun, Yao Sheng, Jingman Wang, Jiahui Jin, Fei Li, Lingyun Chen, Di Zhou, Yongchao Tan, Quanwei Wang, Zhao Xu, Haibao Li, Pin Wang, Jun Cui. The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4062.
Abstract 1988: FAP-targeted non-internalising drug conjugates: A comparative evaluation between small molecules, antibodies and peptides
Authors: Aureliano Zana, Claudia Puig Moreno, Ettore Gilardoni, Dario Neri, Samuele Cazzamalli
Journal: Cancer Research (2023)

Abstract Conventional cancer chemotherapy relies on the use of cytotoxic drugs which are not designed and capable of selective accumulation to neoplastic lesions. The conjugation to tumour-targeting delivery vehicles has been proposed as a strategy to enhance the therapeutic index of potent cytotoxic drugs. To date, fifteen Antibody-Drug Conjugate products have received marketing approval for the treatment of solid and liquid human malignancies. We present an in vivo comparative evaluation of ADCs against products based on small organic delivery vehicles (Small Molecule-Drug Conjugates, or SMDCs) or on tumour-targeting peptides (Peptide-Drug Conjugates, or PDCs). All products are designed to target and to be activated by Fibroblast Activation Protein in the tumour microenvironment. Our results reveal that both targeted ADC and SMDC products mediate potent anti-cancer activity and complete tumour remission in a FAP-positive preclinical murine model of cancer, when administered at the same molar dose. Non-targeted albumin and antibody conjugates included in our comparative studies delayed tumour growth but presented suboptimal anti-cancer efficacy in the same cancer model. Our results indicate that both FAP-targeted ADCs and SMDCs are promising product candidates for the treatment of multiple human malignancies. Citation Format: Aureliano Zana, Claudia Puig Moreno, Ettore Gilardoni, Dario Neri, Samuele Cazzamalli. FAP-targeted non-internalising drug conjugates: A comparative evaluation between small molecules, antibodies and peptides [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1988.
Abstract 4918: Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms
Authors: Hongye Zou, Yatian Yang, Demin Cai, Hong-Wu Chen
Journal: Cancer Research (2023)

Abstract Natural compounds such as ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have also been at several clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) in tumor cells severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target in castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC). Previous studies implicated UA and digoxin as potential RORγ antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. UA also showed potent anti-growth effects in AR-positive prostate cancer cells compared to AR-negative prostate cancer cells. In TNBC cells, UA but not digoxin alters RORγ-regulated cell proliferation and apoptosis gene programs. Together, our study shows for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in prostate cancer and TNBC cells. Our finding that RORγ is a direct target of UA in specific type of cancer will help select patients with tumors that likely respond to UA treatment. Citation Format: Hongye Zou, Yatian Yang, Demin Cai, Hong-Wu Chen. Natural compounds ursolic acid and digoxin exhibit anti-cancer effects through nuclear receptor RORγ-dependent and -independent mechanisms. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4918.
Abstract 6497: Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States
Authors: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Zara Hassan, Poornima Ramadas
Journal: Cancer Research (2023)

Abstract Background: Survival outcome in Non-Hodgkin lymphoma (NHL) is significantly better in earlier stages, compared to advanced stages. Early identification of signs and symptoms, and prompt specialist availability and referral, are crucial for diagnosis and treatment at earlier stages. Mounting physician shortages are a growing concern, and we sought to analyze their effect on NHL mortality rates. Methods: We extracted data on the age-adjusted mortality rate (AAMR) and crude incidence rate (CIR) of NHL for all U.S. states and the District of Columbia from the Center for Disease Control (CDC) Wide-ranging Online Data for Epidemiologic Research (WONDER) database (2017-2019). Nevada was excluded due to missing information. Data on the state-wise number of primary care physicians (PCPs) was obtained from the Association of American Medical Colleges (AAMC) state physician workforce data report (2020), and of Hematology/Oncology specialists (HOs) was gathered from the National Provider Identifier (NPI) registry (2020). The number of PCPs and HOs per each NHL incidence (PCP/CIR, HO/CIR respectively) was then calculated. Correlations were analyzed using Pearson’s coefficient. Statistical analysis was performed using VassarStats. Results: Median AAMR for NHL in the US was 5.15 (IQR 4.35, 5.95) per 100, 000 population. The median number of PCP and HO per each case of NHL incidence was 4.32 (IQR 3.43, 5.21), and 0.28 (IQR 0.1, 0.37) respectively. States with fewer PCPs per each NHL incidence had higher AAMR (r=-0.37, p=0.007). States with a lower number of HOs per each NHL incidence had higher AAMR (r=-0.41, p=0.003) Conclusions: Based on the analysis, the availability of a lower number of PCPs and HOs per each NHL incidence is associated with increased AAMR of the disease. This data may strengthen the need for intensification of focus on decreasing the soaring physician shortages in the states, in order to help decrease the overall mortality associated with NHL. Citation Format: Shiva Jashwanth Gaddam, Udhayvir Singh Grewal, Zara Hassan, Poornima Ramadas. Availability of healthcare providers and its association with survival outcomes in non-Hodgkin lymphoma in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6497.
Abstract SY32-03: Overcoming PARP inhibitor resistance through rational combinations in the clinic
Authors: Timothy A. Yap
Journal: Cancer Research (2023)

Abstract Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. The therapeutic landscape of antitumor agents targeting the DDR has rapidly expanded to include inhibitors of key mediators of DNA repair and replication beyond PARP, such as ATR and WEE1. Dr Yap will cover the latest advances in biomarker-driven synthetic lethal combination treatment strategies for different cancers. He will discuss efforts to optimize combination therapies that are ongoing across a range of cancers, involving the development of predictive biomarkers of response, assessment of the mechanisms underlying resistance, and the evaluation of rational, tolerable combinations with novel molecularly targeted agents, immune-checkpoint inhibitors and antibody drug conjugates. Citation Format: Timothy A. Yap. Overcoming PARP inhibitor resistance through rational combinations in the clinic. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY32-03.
Abstract 4983: Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a targetable vulnerability
Authors: Adam J. Sugarman, Luong Do Huynh, Antonio Di Cristofano
Journal: Cancer Research (2023)

Abstract Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we have analyzed gene expression profiles from a genetically engineered ATC mouse model and from two human patient datasets, and have found consistent and coordinated upregulation of several genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate nucleotides, glutathione and glycine. We have used a combination of cell line and in vivo approaches to assess the role of this pathway in the progression and maintenance of ATC and the effect of its inhibition on tumor behavior. Genetic and pharmacological inhibition of both MTHFD2 and SHMT2, key enzymes of the mitochondrial arm of the one-carbon pathway, rendered mouse and human ATC cells auxotroph for glycine and led to significant inhibition of tumor cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool leading to arrest in S phase. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic blockage of the one-carbon pathway dramatically impaired tumor growth in vivo, both in immunocompetent allograft models and in immunocompromised xenograft models of ATC. Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes. Citation Format: Adam J. Sugarman, Luong Do Huynh, Antonio Di Cristofano. Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a targetable vulnerability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4983.
Abstract 1653: Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer
Authors: Maria del Carmen Chacon Castro, Eranda Berisha, Narges Salamat, Li Zhang
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. KRAS mutations and LKB1 inactivation commonly occur in NSCLC and are associated with poor prognosis. Several studies enunciate the role of the immune system in lung cancer progression through cancer cells' ability to escape immune surveillance. Therefore, understanding NSCLC progression requires the examination of the molecular mechanisms behind this process. The importance of oxidative phosphorylation (OXPHOS) and mitochondrial metabolism in lung cancer has been continuously emphasized; OXPHOS and mitochondrial biogenesis markers predict low survival in NSCLC patients. Additionally, heme is an essential molecule in the OXPHOS pathway, and previous studies have shown that heme sequestration using heme sequestering protein 2 (HeSP2) arrests tumor progression. HeSP2 can potentially normalize the tumor immune microenvironment (TIME) via multiple mechanisms including the normalization of vessels which may promote immune cell infiltration, the reduction of hypoxia which may promote antitumor immune function, and the reduction of heme levels which potentially decreases the production of immunosuppressive enzymes requiring heme as a cofactor. In this study, control and HeSP2-treated tumors generated from a genetically engineered mouse model LSL-KrasG12D LKB1-/- (LSL-KRASG12D; LKBloxP/loxP; LSL-Luciferase (KLLuc) infected with AdenoCre virus and sacrificed at 10 months were used for immunohistochemical analysis. We examined immune markers under HeSP2 treatment to determine the immune system response to heme targeting and its effects on tumor progression. Results demonstrated that HeSP2 can modulate the tumor immune microenvironment increasing the levels of immune markers, which suggests that heme targeting can potentiate immunotherapy efficacy in lung cancer treatment. Citation Format: Maria del Carmen Chacon Castro, Eranda Berisha, Narges Salamat, Li Zhang. Heme sequestration modulates the tumor immune microenvironment in KRAS mutation/LKB1 inactivation non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1653.
Abstract 2039: Predicting abundance and expression of immune cells in patients’ head &amp; neck tumor microenvironment from blood single-cell transcriptomics
Authors: Yingying Cao, Tiangen Chang, Fiorella Schischlik, Sanju Sinha, Kun Wang, Peng Jiang, Eytan Ruppin
Journal: Cancer Research (2023)

Abstract The tumor microenvironment (TME) is a key determinant of immunotherapy efficacy, yet, not readily accessible. Here, we ask if the immune cell fractions (ICFs) and gene expression patterns in the TME can be predicted from the blood single-cell RNA sequencing (scRNA-Seq) data. To the best of our knowledge, the immune status of the TME has not been comprehensively evaluated and predicted from the blood previously. Addressing this challenge, we analyzed 26 paired head and neck squamous cell carcinoma (HNSCC) patients matched blood and tumor samples with CD45+ scRNA-Seq data and clinical information. We developed a machine learning predictor of ICFs and gene expression levels of major immune cell types in the TME from the matching blood transcriptomics and pertaining clinical information, termed the Tumor Immune MicroEnvironment Predictor (TIMEP). We find that the ICFs, all 11 major immune cell types in the TME were predictable from the blood. 17-47% genes expressed in different immune cells were predictable from the blood, with the highest coverage in dendritic cells and helper, cytotoxic and regulatory T cells. Furthermore, the ICF ratio (ICFR) signature of (Treg - Bmemory)/(Treg + Bmemory) in the TME, as predicted from the blood, can robustly predict the response to immune checkpoint blockade (AUC &amp;gt; 0.72 on three independent single-cell and bulk expression datasets). These results are the first to demonstrate the feasibility of employing single-cell transcriptomics liquid biopsy to predict the immune status in patients TME in patients, facilitating future personalized cancer precision therapy. Citation Format: Yingying Cao, Tiangen Chang, Fiorella Schischlik, Sanju Sinha, Kun Wang, Peng Jiang, Eytan Ruppin. Predicting abundance and expression of immune cells in patients’ head &amp; neck tumor microenvironment from blood single-cell transcriptomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2039.